Friday, 9 December 2016

The MS Society Christmas Concert at St Paul's Cathedral last night was very slick and uplifting. The concert is part of their ambitious Stop-MS campaign to raise £100M over 10 years for MS Research.

The concert was layered around several Christmas stories written by Abi Morgan about people living with MS. Abi is a very successful play and screen writer. All the stories were read by professional actors, who were stunningly good at bring out the emotion in each story. My only complaint is that the stories were slightly sugar coated, or may be marzipan-coated a more appropriate term for Christmas. Dare I say the stories represented a 'rose-tinted' view of what Christmas is like for people living with MS.

I am currently on day 3 of a teaching course we run to teach people about MS. Yesterday, Dr Clarence Liu, our neurorehabilitation expert, was unable to give his talk, which I delivered on his behalf. One of the cases of his I presented represents the under-belly of MS; neglected MS.

Interestingly, I read a deeply moving account of a neglected patient with breast cancer in this week's NEJM. You can easily do a search and replace substituting 'breast cancer' with 'multiple sclerosis' and the messages will be the same. How do we as a society lift ourselves up and not forget the neglected people with disease? How do we improve our health and social services to make sure these people are found and looked after better?

I have picked some excerpts from the perspective piece, but I would recommend you click on the link and read the full article; it highlights why we need to be more human (#BeHuman).

.... My first thought, as I viewed the CT images, was a somewhat fantastic notion that the tumor on the monitor screen could not possibly be real. It obliterated not just the area where the breast should have been but most of the chest wall....

..... Even in the United States, such a presentation is a common enough occurrence that any first-year oncology fellow can tell you its name: “neglected breast cancer,” a name that implies that the woman has neglected to take proper action to treat the cancer.

..... The minute I walked through the patient’s door, I knew: the pressured speech and tangential associations of bipolar disorder hit me with concussive force....

...... One of these melodies was familiar: at first, the patient had not believed it could be cancer, although she’d acknowledged the possibility. She’d had a plan to use various alternative therapies and to eventually have a biopsy if they hadn’t worked; she thought the fact that the therapies weren’t working meant that it must actually be an infection......

...... A second melody told the story of the terror she’d experienced as a very young child witnessing a relative’s cancer treatment and its effects, including hair loss. She feared having similar treatments forced on her. Her appearance was important to her. I noticed that despite being in the hospital, she had taken the time to apply makeup. She wore bright red lipstick, but the color spilled over the edges of her lips, as if a child had colored outside the lines. I later realized she must have had to apply it with her nondominant left hand — she’d lost the function of her right arm because the tumor had destroyed the brachial plexus.....

...... Her family had their own refrain to share, describing a loving mother and a vibrant member of the community. Her grown children were now raising young children of their own. Only in recent years had they started observing unusual behaviors. Eventually, out of love and concern, they’d had her involuntarily committed for a psychiatric evaluation. She’d felt betrayed by her family, and they continued to feel horrible guilt over that decision. She had read extensively about patients’ rights so that she would never again be hospitalized against her will.....

..... She continued to refuse to allow any health care or hospice staff into her home. I prescribed comfort medications, but she would rarely let her family administer them. When the exhausted family could cope no longer, out of desperation they brought her to the hospital. When I went to see her, she was sleeping comfortably, having finally accepted pain medication. I felt undeserving of the hugs her family gave me. She died peacefully 2 days later......

..... Her death left me with feelings of profound failure. What good were targeted therapies when her coexisting mental illness prevented her from taking them? And I had been unable to palliate her suffering until her very last days of life. Oncologists don’t just prescribe chemotherapy — a large part of our practice involves caring for people at the end of life. I could not provide that care because I lacked the tools and training to overcome the barrier of mental illness.....

.... Before my patient died, her family had told me that they hadn’t found out about the tumor in her breast until they asked one day about the strange bulge beneath her shirt. They hadn’t realized how advanced her disease was until the day I first met her in the hospital. They asked me what the outcome would have been if she had not hidden it from them and had sought care earlier...

..... I was tempted to answer this question academically, telling them about success rates of the latest neoadjuvant four-drug combination regimens, outlining a typical course of neoadjuvant chemotherapy, surgery, adjuvant radiation therapy, and 1 year of adjuvant trastuzumab. But I imagined the patient coming to me in a fictional past at an earlier stage of disease. Without treatment of her mental illness, she would have been extremely unlikely to agree to, let alone complete, such a course of therapy. She might have had surgery if she had presented when the cancer was at an operable stage, but she might not have agreed to that either. And regardless, without a full course of adjuvant therapy for the high-risk, HER2-positive, ER-negative tumor, within months to years she would inevitably have had metastatic disease.....

..... So instead, I found myself gently answering, “The same. I think it would have been the same.”......

...... The family nodded in agreement, saying that’s what they thought, too — that in the end, the cancer was but the saddest final chapter in the devastating story of untreated mental illness, the true neglect......

Thursday, 8 December 2016

PML may not be an intractable problem; could immunotherapy be the solution? #ResearchSpeak #MSBlogAt present we don't have an anti-viral agent that works against the JC virus that causes PML (progressive multifocal leukoencephalopathy). Therefore we have to rely on your own immune system to fight and clear the virus if you develop PML. This is why we wash out natalizumab with plasma exchange, or stop the immunosuppressive, when somebody develops PML. A problem arises when we can't reconsititute CNS immunosurveillance or your immune system. The latter can happen with PIRTs (pulsed immune reconstitution treatments) or in people with persistent lymphopaenia. This is where immunotherapies are needed. One strategy is to give unfortunate people with PML in this situtation donor anti-JCV lymphocytes that are matched to their HLA (human leukocye antigens) to fight the infection. In short this is a immune transplant, i.e. giving them donor-matched T-lymphocytes to fight JCV. The study below presented at last year's American Society of Haematology (ASH) meeting tested this approach in two patients. They used T-cells that were designed to attack BK virus that cross-reacts with JCV. In both these patients the approach worked. Logistics of this kind of therapy make it difficult. I advised lymphocyte donation a few year's ago in patient with lupus with persistent lymphopaenia who had developed PML. By the time her team had mobilised an HLA-matched bone marrow donor who was JCV-positive the patient was in extremis and died before she could receive the donor lymphocytes. The logistics of immunotherapy for PML are not insignificant and ideally need to be established before hand so as not to delay treatment. In other words we need to screen potential lymphocyte donors beforehand so that we can call them in at short notice to harvest their lymphocytes. The other option is to rely on Pharma to create a bank of HLA-specific cytotoxic T-lymphocytes that are frozen and cane be mobilised within 24-48 hours as a licensed treatment for PML. The cost of the latter will probably be in the $100,000s compared to the former that will only cost £1,000s and can be bolted onto a bone marrow donation register. The latter can be funded by charities and former will need large investment from Pharma and regulatory approval. There is clearly an unmet need in the management and treatment of PML; we probably need to explore both approaches.If I had more energy and time I would try and set this up. London would be a good place to do this as we have the largest bone marrow donor register in the UK and the highest population density in the UK. Any volunteers?

Progressive multifocal leukoencephalopathy (PML) is a rare and often fatal demyelinating disorder of central nervous system caused by JC virus reactivation in patients with severe defects of cellular immunity. JC virus is genetically similar to BK virus. Both JC and BK virus express large tumor antigen (LT), small tumor antigen (ST), and the capsid proteins, VP1, VP2 and VP3 during replication. Due to antigenic epitope homology, ex vivo expanded BK virus specific T cells can also target JCV, especially for VP1 and LT. We developed a rapid, effective and GMP-compliant BK virus specific cytotoxic T lymphocyte (CTL) expansion method from peripheral blood mononuclear cells. Donor mononuclear cells were stimulated with a BK virus peptide mix in the presence of IL-2, IL-7 and IL-15 for 14 days. At the end of culture, the cells were harvested and cryopreserved until use.Here, we report the first two cases of PML treated with BK virus specific CTL from the most closely HLA-matched donor.Case 1. A 32-year-old female with a diagnosis of FLT3+ acute myeloid leukemia underwent double cord blood transplantation. Her post-transplant course was complicated by acute graft versus host disease involving skin and gastrointestinal tract, HHV-6 infection and BK virus related hemorrhagic cystitis. Twenty months after transplantation she presented with left-sided extremity weakness, slurred speech and mental confusion. The physical examination revealed ataxic gait and weakness of left lower extremity. MRI revealed abnormal pattern of parenchymal enhancement and signal abnormality in the posterior fossa, predominantly involving cerebellum and brain stem. Lumbar puncture revealed low levels of JC virus DNA (130 copies/ml). Repeat MRI three weeks later showed progression in the peduncle and right cerebellum with an increase in the CSF JC virus load to 700 copies/ml. At this point the patient received 105/kg BKV-specific CTLs expanded from a 3/6 HLA-matched allogeneic donor. There was no infusion-related toxicity. Two weeks later, there was a significant reduction in the JC virus titer to 78 copies/ml (limit of detection 72 copies/mL). HLA BW6+ donor CD4+ and CD8+ T-cells could be detected in the CSF 2 weeks after infusion, confirming that BK virus CTLs can home to inflammatory sites in the central nervous system. The lymphocytes in CSF showed a distinct phenotypic profile, mainly composed of recipient CD56bright NK cells and a mixture of donor and recipient CD4+ and CD8+ T cells. Donor T cells in CSF expressed very high levels of PD1 and CXCR3 compared to peripheral blood T-cells. Four weeks from the infusion, the neurological symptoms have resolved and repeat MRI confirmed near complete resolution of the lesions. The patient received a second CTL infusion 3 weeks after the first for persistent low positive JCV in the CSF. The patient remains essentially asymptomatic 4 months after BK virus specific CTL infusion with intermitted low positive JC virus DNA titers in the CSF. Donor T cells continue to be present in the CSF.Case 2. A 73-year-old female with JAK2 positive myeloproliferative disorder on treatment with ruxolitinib for 8 years presented with altered mental state, blurred vision and unsteady gait. MRI revealed parieto-occipital subcortical signals in left hemisphere extending to the posterior temporal lobe suggestive of PML. JC virus load in the CSF was 230,000 copies/ml. She received a 2/6 HLA-matched allogeneic BK virus specific CTLs. Three weeks after infusion JC virus titer in the CSF decreased to 5,200 copies/ml and her condition stabilized. The MRI remained stable. Donor-derived CD4+ and CD8+ T cells were detected in the CSF, with high expression of PD1 and inflammatory chemokines on T cells. The patient received a second dose of BK virus specific CTL from the same donor one month after the first infusion. The CSF viral load reduced further to 800 copies/ml but the there was no clinical or radiological improvement, suggestive of irreversible CNS damage. The patient remains alive.In this proof-of-principle study, we have used ex vivo expanded BK virus specific CTL to target PML, a disease without viable treatment strategies and with a universally fatal outcome. Both patients showed a remarkable reduction in the viral load and there was near complete resolution of symptoms and MRI findings in one case. Use of third party partially HLA-matched BK virus specific CTLs to treat PML holds promise.

The objective was to determine whether CD52 lymphocyte depletion can act to promote immunological tolerance induction via intravenous antigen administration such that it could be used to either: improve efficiency of inhibition of MS or to inhibit secondary autoimmunities that may occur following alemtuzumab use in multiple sclerosis. Relapsing experimental autoimmune encephalomyelitis was induced in ABH mice and immune cell depletion was therapeutically applied using mouse CD52 or CD4 (in conjunction with CD8 or CD20) depleting monoclonal antibodies. Immunological unresponsiveness was then subsequently induced using intravenous central nervous system antigens and responses assessed clinically. A dose-response of CD4 mAb depletion indicated that 60-70% functional CD4 T cell depletion achieved in perceived failed trials in MS, was perhaps too low to even stop disease in animals. However, more marked (~75-90%) physical depletion CD4 T cells via CD4 and CD52 depleting antibodies inhibited relapsing disease. Surprisingly in contrast to CD4 depletion, CD52 depletion blocked robust immunological unresponsiveness via a mechanism involving CD8 T cells. Although efficacy was related to the level of CD4 T cell depletion, the observations that CD52 depletion of CD19 B cells was less marked in lymphoid organs than in the blood provides a rational for the rapid B cell hyper-repopulation that occurs following alemtuzumab administration in MS. That B cells repopulate in the relative absence of T cell regulatory mechanisms that promote immune tolerance may account for the secondary B cell autoimmunities, which occur following alemtuzumab treatment of multiple sclerosis.

Recently someone on the blog was complaining about TeamG research output when we posted on our paper about what to call some one with MSYou said"What causes progression and how can it be treated, making Alemtuzumab safer and more effective, encouraging them brain to kick-start repair.... so far Team G is in wizard of Oz land - big voice, until you pull back the curtain. Time for some real research Team G!"To address your comment how do you make "Alemtuzumab safer and more effective" You have got your wish.To ask how you make alemtuzumab safer, you first have to understand why it is not safe and to have ideas. You have to have the data, but it does not always easily come to hand or do you have to do some detective work?The safety issues relating to alemtuzumab are:

infusion reactions,

consequences of long term blanket immunosuppression and

secondary autoimmunities that occur in about 50% of people within five years.

How do you get rid of all those problems?...Simple!.Use another drug that does not have these problems...However, to be serious....Ask the many people who have had great benefit for the alemtuzumab and I am sure they will say it was worth it.However to get rid of the safety issues you first need to understand what they are and how are they caused.We know how to turn off an autoimmune response within a day in the beasties. To do this we simply reduce the T cell number and then re-induce immune tolerance by intravenously injecting the target antigen. Sounds simple...it is.The way we do this is deplete CD4 T cells but we asked the question is could we use CD52 depletion instead?Why? Because we could not get anybody to give us access to a CD4 depleting However, the answer was surprsingly no.We found essentially three things(a) CD52 depletes CD4 T cells and inhibits relapsing EAE

(b) CD52 depletion did not deplete B cells in lymph glands as much as it did in the blood (c) It blocked the development of unresponsiveness in our hands and this was probably because it depleted a CD8 regulatory T cell population that was inducing tolerance.What does this mean?(a) If MS is caused by CD4, Th1/TH17 T cells then these will be inhibited by alemtuzumab...(b) The problem with alemtuzumab is that it causes B cell autoimmunities like Graves Disease (hyperactive thyroid disease), ITP (blood clotting problem). This means you have have blood tests every month for 4 years......So if the antibody that does not clear B cells out lymph glands/bone marrow it means that once the antibody disappears ,which takes about a month then B cell, that have escaped destruction can rush out of the lymph glands and they can then fill up the blood with new cells and they can overshoot...This is the elephant in the Room.When the B cells repopulate they are doing so when there is a limited T regulation, in this case a CD8 T cell population, which is destroyed by the CD52 depletion. These used to be called CD8 T suppressor cells. So is this the reason why people with MS get lots of secondary B cell autoimmunities...Prompted some delving and it was found that not only was B cell autoimmunites a problem but anti-drug responses occured with staggeringly high frequency. Do they affect treatment response?However, it pointed us to places that allowed us to understand how alemtuzumab-probably induces autoimmunities and works in MS,But that's another story to be reported soon

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